The present invention is relevant to the fields of human and veterinary medicine, physiology and biochemistry, particularly in the regulation of cellular proliferation and lipid metabolism in a mammal.
A vast array of specific metabolic, developmental, and catabolic processes appear to be directly or indirectly regulated in vivo by comparatively small molecules such as steroids, retinoids and thyroid hormones. The mechanism whereby a single such compound can contribute to the regulation of numerous different cellular events was the subject of much speculation until relatively recently, when it was discovered that these compounds each share the ability to bind to transcriptionally active proteinaceous receptors. These protein receptors, in turn, are able to bind specific cis-acting nucleic acid regulatory sequence regions, termed response elements or RE""s, located upstream of the coding sequence of certain genes and to activate the transcription of these genes. Thus, the proteinaceous receptors can serve as specific, ligand-dependent regulators of gene transcription and expression.
The amino acid sequences of these various receptors were quickly found to share regions of homology, thus making each such receptor a member of a family of ligand-modulated receptor molecules. This family has been termed the steroid superfamily of nuclear hormone receptors; nuclear, because the receptors are usually found in high concentration in the nucleus of the cell.
Further study of the structural and functional relationship between the nuclear hormone receptors has shown certain characteristics in common between them in addition to sequence homology. See e.g., Evans et al. Science 240:889-895 (1988). As stated above, the nuclear hormone receptors are able to bind to cis-acting regulatory elements present in the promoters of the target genes. The glucocorticoid, estrogen, androgen, progestin, and mineralcorticoid receptors have been found to bind as homodimers to specific response elements organized as inverted repeats.
Another class of nuclear hormone receptors, which includes the retinoid receptor RAR (retinoic acid receptor), the thyroid receptor, the vitamin D receptor, the peroxysome proliferator receptor, and the insect ecdysone receptor bind the response element as a heterodimer in conjunction with the retinoid X receptor (RXR), which is positively activated by 9-cis retinoic acid. See Mangelsdorf, et al., The Retinoid Receptors in The Retinoids: Biology, Chemistry and Medicine Ch.8 (Sporn et al., eds. 2d ed., Raven Press Ltd. 1994); Nagpal and Chandraratna, Current Pharm. Design 2:295-316 (1996), which are both incorporated by reference herein. The retinoid receptors RAR and RXR, like many nuclear hormone receptors, exist in a number of subtypes (RARxcex1, RARxcex2, RARxcex3, and RXRxcex1, RXRxcex2, and RXRxcex3). Additionally, each subtype may exist in different isoforms.
Another such receptor is a relatively recently characterized nuclear hormone receptor termed farnesoid X-activated receptor (FXR). Foreman et al., Cell 81:687-693 (1995) have demonstrated that this receptor termed farnesoid X-activated receptor (FXR), is activated by farnesol and related molecules. This reference is hereby incorporated by reference herein. FXR expression is largely restricted to the liver, gut, adrenal gland, and kidney.
Common to other nuclear hormone receptors, the amino acid sequence of FXR reveals a conserved DNA-binding domain (DBD) and ligand-binding domain (LBD). The LBD comprises subdomains responsible for ligand binding, receptor dimerization, and transactivation. Additionally, cells expressing chimeric proteins that contain the LBD of FXR fused to the DBD of the yeast GAL4 transcription activator did not transcribe a reporter gene containing a GAL4 response element unless the FXR construct was coexpressed with another protein comprising the dimerization and ligand binding subdomains of RXR. These data suggested that FXR and RXR interact to form a transcriptionally active dimer. No interaction was seen between FXR and any other nuclear hormone receptor. Id.
FXR has been recently discovered to be an important regulator of bile acid synthesis. When bound by an appropriate ligand FXR is activated, and functions to regulate the expression of Cyp7a, thereby controlling a key stage in the degradation of cholesterol, the precursor of the bile acids and the steriod hormones. See Wang, et al., Molec. Cell 3:543-553 (May 1999), hereby incorporated by reference herein.
The present invention is directed to silicone-containing organic compounds is and compositions comprising such compounds having the general structure indicated in Formulae 1-4, infra. Such compounds are useful to modulate the transcription-regulating activity of a nuclear hormone receptor, such as, without limitation, a retinoic acid receptor (RAR), a retinoid X receptor (RXR), a farnesoid receptor (FXR), perioxisome proliferator activated receptor (PPAR) and the like. Certain such compounds are ligands of either or both an RAR or an RXR, and able to cause the retinoid receptor to suppress, inhibit, or stimulate the transcription of a given target gene. Preferably, in this embodiment of the present invention the claimed compounds are substantially specific in their activity towards either RXR or RAR, and do not activate or inhibit any other nuclear hormone receptor.
Certain compounds of the present invention may have activity at one or more nuclear hormone receptor other than a retinoid receptor, such as, without limitation, FXR, PPAR, TR, DAX, CAR. Preferably, the compound is active as a modulator of FXR activity. It is also preferred, although not essential, that the compound is not substantially active as a modulating ligand of other nuclear hormone receptors.
It has also been discovered that the compounds of the present invention have activity as agonists, antagonists, or inverse agonists of the transactivation activity of nuclear hormone receptors. Certain compounds of the present invention have RAR and/or RXR agonist activity in a transactivation assay using a reporter gene as a transcription template.
Certain compositions of the invention comprise a compound active as an FXR agonist or antagonist that is able to modulate concentrations of plasma cholesterol in a mammal. In another embodiment the FXR agonist may be used to increase the concentration of cholesterol within a hypocholesteremic mammal. As stated above, FXR has been discovered to inhibit Cyp7a expression when bound and activated by bile acids. Thus, an antagonist of FXR would prevent the bile acid-initiated inhibition of Cyp7a synthesis.
The nuclear hormone receptor ligands of the present invention may be receptor agonists, receptor antagonists, or receptor inverse agonists. By xe2x80x9cagonistxe2x80x9d is meant that the ligand stimulates a ligand-dependent receptor-characteristic activity above any baseline levels present in the absence of ligand. By xe2x80x9creceptor-characteristic activityxe2x80x9d is meant the direct or indirect inhibition or stimulation of gene expression, which expression is regulated by the receptor in question. By xe2x80x9cantagonistxe2x80x9d is meant that the ligand binds to the receptor and functions as a competitive or non-competitive inhibitor of receptor-characteristic agonist activity. By xe2x80x9cinverse agonistxe2x80x9d or xe2x80x9creverse agonistxe2x80x9d is meant that the ligand will bind to the receptor in question and cause the suppression of receptor activity lower than the amount of activity seen in the absence of receptor ligand.
Thus, the present invention pertains to compositions comprising, consisting essentially of, or consisting of a compound selected from the group consisting of Formulas 1, 2, 3 and 4 
wherein the dashed line represents a bond or absence of a bond;
X is S, O, NRxe2x80x2 where Rxe2x80x2 is H or alkyl of 1 to 6 carbons, or
X is (C(R1)2)n where R1 is H or alkyl of 1 to 6 carbons, and n is an integer having the value of 0 or 1;
R2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 12 carbons, or alkylthio of 1 to 12 carbons, benzyloxy or C1-C12 alkylbenzyloxy;
R3 is hydrogen, lower alkyl of 1 to 6 carbons or F; m is an integer having the value of 0-3;
o is an integer having the value of 0-4 when the dashed line represents absence of a bond, and 0-3 when the dashed line represents a bond;
R3xe2x80x2 is hydrogen, lower alkyl of 1 to 6 carbons, F or R3xe2x80x2 is hydrogen, lower alkyl of 1 to 6 carbons, F or (R15)r-phenyl, (R15)r-naphthyl, or (R15)r-heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is an integer having the values of 0-5;
R4 is alkyl of 1 to 8 carbons, or phenyl;
Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
R15 is independently H, F, Cl, Br, I, NO2, N(R8)2, NH(R8), COR8, NR8CON(R8)2, OH, OCOR8, OR8, CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or trialkylsilyloxy group where the alkyl groups independently have 1 to 6 carbons;
A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH, NO2, P(O)(OH)2, P(O)(OH)OR8, P(O)(OR8)2, SO2OH, SO2(OR8), COOR8, CONR9R10, xe2x80x94CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, xe2x80x94COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons, or a pharmaceutically acceptable salt of said compound.
Other aspects and embodiments of the invention are contained in the disclosure that follows and the claims that conclude this specification.
The present invention is directed to compositions capable of modulating the activity of a mammalian nuclear hormone receptor, preferably the human RXR, RAR or FXR receptor proteins.
Such compositions comprise compounds that will bind a nuclear hormone receptor, thereby affecting the biological activity of the receptor, either directly or by blocking the ability of a naturally occurring receptor ligand to exert its effects on the receptor. In certain embodiments, the compositions of the present invention will also contain a pharmaceutically acceptable excipient or carrier. The compositions of the present invention may comprise antagonists, agonists, or inverse agonists of the receptor. Preferably, although not necessarily, the compounds have activity at a single receptor type and have no substantial activity at other nuclear hormone receptors.
Also included within the scope of the invention are aspects directed to compositions comprising a pharmaceutically acceptable composition comprising a receptor agonist, antagonist or inverse agonist for treatment of a medical condition. In one aspect, the receptor is an RAR agonist, and the medical condition is a disease or condition, such as acne, psoriasis, rheumatoid arthritis and viral infections. RAR active compounds are well known to be useful for the treatment of such conditions.
In another aspect the composition comprises a pharmaceutically acceptable composition comprising an FXR antagonist, as disclosed herein. Such a compound, effectively blocking the inhibition of bile acid synthesis by bile acids, would promote the synthesis of bile acids though the breakdown of cholesterol.
Specifically, the compounds of the present invention are silicone-containing organic compounds of the general structure indicated below.
The compounds of this invention are useful as regulators of cell proliferation and differentiation and of lipid metabolism, and particularly as agents for treating dermatoses, such as acne, Darier""s disease, psoriasis, icthyosis, eczema and atopic dermatitis, and for treating and preventing malignant hyperproliferative diseases such as epithelial cancer, breast cancer, prostatic cancer, head and neck cancer and myeloid leukemias, for reversing and preventing atherosclerosis and restenosis resulting from neointimal hyperproliferation, for treating and preventing other non-malignant hyperproliferative diseases such as endometrial hyperplasia, benign prostatic hypertrophy, proliferative vitreal retinopaythy and dysplasias, for treating autoimmune diseases and immunological disorders (e.g. lupus erythematosus), for treating chronic inflammatory diseases such as pulmonary fibrosis, for treating and preventing diseases associated with lipid metabolism and transport such as dyslipidemias, hypercholesterolemia and hypocholesterolemia, for promoting wound healing, for treating dry eye syndrome and for reversing and preventing the effects of sun damage to skin.
In the treatment of dermatoses, it will generally be preferred to administer the drug topically, though in certain cases such as treatment of severe cystic acne, oral administration may also be used. Any common topical formulation such as a solution, suspension, gel, ointment, or salve and the like may be used. Preparation of such topical formulations are well described in the art of pharmaceutical formulations as exemplified, for example, Remnington""s Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pa. For topical application, these compounds could also be administered as a powder or spray, particularly in aerosol form.
If the drug is to be administered systemically, it may be confected as a powder, pill, tablet or the like, or as a syrup or elixir for oral administration. For intravenous or intraperitoneal administration, the compound will be prepared as a solution or suspension capable of being administered by injection. In certain cases, it may be useful to formulate these compounds in suppository form or as an extended release formulation for deposit under the skin, as a transdermal delivery system, or by intermuscular injection.
Other medicaments can be added to such topical formulation for such secondary purposes as treating skin dryness, providing protection against light; other medications for treating dermatoses, preventing infection, reducing irritation, inflammation and the like.
Treatment of dermatoses or any other indications known or discovered to be susceptible to treatment by retinoic acid or farnesoid receptor modulators will be effected by administration of the therapeutically effective dose of one or more compounds of the instant invention. A therapeutic concentration will be that concentration which effects a reversal or inhibition of the particular condition, or retards its expansion. In certain instances, the drug potentially could be used in a prophylactic manner to prevent onset of a particular condition. A given therapeutic concentration will vary from condition to condition and in certain instances may vary with the severity of the condition being treated and the patient""s susceptibility to treatment. Accordingly, a given therapeutic concentration will be best determined at the time and place through routine experimentation. However, it is anticipated that in the treatment of, for example, acne, or other such dermatoses, that a formulation containing between 0.001 and 5 percent by weight, preferably about 0.01 to 1% will usually constitute a therapeutically effective concentration. If administered systemically, an amount between 0.01 and 100 mg per kg body weight per day, but preferably about 0.1 to 10 mg/kg, will effect a therapeutic result in most instances.